Targeting PEPT1: a novel strategy to improve the antitumor efficacy of doxorubicin in human hepatocellular carcinoma therapy

Abstract

Proton coupled oligopeptide transporter 1 (PEPT1) is a member of the peptide transporter superfamily and plays important role in the absorption of oligopeptide and peptidomimetic drugs. Our previous research verified that PEPT1 expressed specifically in human Hepatocellular carcinoma (HCC) tissue and cell lines and showed potential transport activity to be a new candidate of the tumor therapeutic target. In this study, we aim to explore the feasibility of a novel tumor target therapeutic strategy: Targeting PEPT1 to improve the antitumor efficacy of Doxorubicin in human HCC therapy. First, Doxorubicin was conjugated with Glycylglycylglycine (Gly-Gly-Gly) − a tripeptide which was known as the substrate of PEPT1 and characterized by HPLC and MS successfully. Doxorubicin-tripeptide conjugate was then observed to clarify the target delivery by PEPT1 and the antitumor effect on human hepatocarcinoma in vivo and in vitro. Furthermore, the improvement of the toxic and side effect of Doxorubicin after conjugation was also evaluated by some biochemical tests. Our results reveal that targeting PEPT1 may contribute to the efficient delivery of Doxorubicin to hepatocarcinoma cells and the reduction of drug toxicity. PEPT1 has the prospect to be a novel target of HCC therapy.

Genetic associations of docetaxel‐based chemotherapy‐induced myelosuppression in Chinese Han population

“…This overlapping indicated that the mutation in rs2297322 was crucial in occurrence of docetaxel‐induced myelosuppression. SLC15A1 codes for Peptide transporter 1 (PepT‐1) and is responsible for absorption of small peptides . It plays an important role in the metabolism of oligopeptide and peptidomimetic drugs.…”

SLC15A2 and SLC15A4 Mediate the Transport of Bacterially Derived Di/Tripeptides To Enhance the Nucleotide-Binding Oligomerization Domain–Dependent Immune Response in Mouse Bone Marrow–Derived Macrophages

“…Thus, POT-mediated substrates have physiological and pharmacological relevance. They may also have significant value as targets in modulating gene expression in the innate immune system and inflammatory response (9–12).…”

Specific expression of proton-coupled oligopeptide transporter 1 in primary hepatocarcinoma-a novel strategy for tumor-targeted therapy

“…PEPT1 is expressed predominantly in the intestine and mediates the absorption of dietary nutrients (di/tripeptide) or peptidomimetic drugs ( 8 ). As PEPT1 is able to transport a broad spectrum of substrates, it is an attractive target for drug delivery ( 9 ). Previous studies on the presence and function of PEPT1 in carcinomas was limited in a number of carcinoma cell lines, including colon carcinoma Caco-2 cells ( 10 ), pancreatic carcinoma cell lines AsPc-1 and Capan-29 ( 11 ), gastric cancer ( 12 ), prostate cancer ( 13 , 14 ) and fibroblast-derived tumor cells ( 15 ), which indicates that PEPT1 may be expressed in other types of cancer cells.…”